Cathepsin cysteine protease inhibitors and their use

ABSTRACT

The present invention relates to compounds and compositions for treating diseases associated with cysteine protease activity. The compounds are reversible inhibitors of cysteine proteases S, K, F, L and B. Of particular interest are diseases associated with Cathepsin S. In addition this invention also discloses processes for the preparation of such inhibitors.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is the National Stage of International Application No. PCT/SE2003/001931, filed Dec. 11, 2003, which claims the benefit of Swedish Patent Application Serial No. 0203712-5, filed Dec. 13, 2002. The contents of both applications are hereby incorporated by reference in their entireties.

The present invention relates to compounds and compositions for treating diseases associated with cysteine protease activity. The compounds are reversible inhibitors of cysteine proteases S, K, F, L and B. Of particular interest are diseases associated with Cathepsin S. In addition this invention also discloses processes for the preparation of such inhibitors.

BACKGROUND OF THE INVENTION

Cathepsin S is a member of the papain superfamily of cysteine proteases which also encompasses Cathepsins B, H, L, O and K. Cathepsin S plays a key role in the processing of invariant chain in MHC class II complexes allowing the complex to associate with antigenic peptides. MHC class II complexes are then transported to the surface of the cell for presentation to effector cells such as T cells. The process of antigen presentation is a fundamental step in initiation of the immune response. In this respect inhibitors of cathepsin S could be useful agents in the treatment of inflammation and immune disorders such as, but not limited to, asthma, rheumatoid arthritis, multiple sclerosis and Crohn's disease. Cathepsin S has also been implicated in a variety of other diseases involving extracellular proteolysis such as the development of emphysema in COPD through degradation of elastin and in Alzheimers disease.

Other Cathepsins notably K and L have been shown to degrade bone collagen and other bone matrix proteins. Inhibitors of these cysteine proteases would be expected to be useful in the treatment of diseases involving bone resorption such as osteoporosis.

The present invention therefore provides a compound of formula (I)

R¹ is independently hydrogen, C₁₋₆alkyl or C₃₋₆ cycloalkyl R² is independently aryl, heteroaryl or a group C₁₋₆alkylR⁹, CO(C₁₋₆alkyl)R⁹ or SO₂(C₁₋₆alkyl)R⁹; where R⁹ is aryl or heteroaryl or R¹ and R² together with the nitrogen atom to which they are attached form a 4 to 7-membered saturated ring optionally containing a carbonyl group, O, S or N atom and optionally substituted by one or more C₁₋₆alkyl, amino, hydroxy, CO₂C₁₋₆alkyl, COC₁₋₆alkyl, halogen, C₁₋₆alkylhydroxy, NR¹⁰R¹¹ where R¹⁰ and R¹¹ are independently hydrogen, C₁₋₆alkyl or together with the nitrogen atom to which they are attached form a 5- or 6-membered saturated ring optionally containing a further O, S or NR¹ group, C₁₋₆alkylNR¹²R¹³ where R¹² and R¹³ are independently hydrogen or C₁₋₆alkyl, CONR¹²R¹³, or optionally substituted by C₁₋₆alkylR⁹, aryl, phenoxy, COaryl, COheteroaryl or a heteroaryl group, the latter six groups being optionally substituted by halogen, amino, hydroxy, cyano, nitro, carboxy, CONR¹²R¹³, SO₂NR¹²R¹³, SO₂R¹², trifluoromethyl, NHSO₂R¹², NHCOR¹², ethylenedioxy, methylenedioxy, C₁₋₆alkyl, C₁₋₆alkoxy, C₁₋₆ alkyl NR¹⁰R¹¹, SR¹² or NR¹⁰R¹¹; Het is a heteroaryl ring chosen from pyridine, pyrimidine, pyrazine, pyridazine or triazine and optionally substituted by halogen, amino, hydroxy, cyano, nitro, carboxy, CONR¹²R¹³, SO₂NR¹²R¹³, SO₂R¹², trifluoromethyl, NHSO₂R¹², NHCOR¹², C₁₋₆alkyl, C₁₋₆alkoxy, SR¹² or NR¹⁰R¹¹; R³ is independently hydrogen, C₁₋₆alkyl or C₃₋₆cycloalkyl; R⁴ is independently hydrogen, C₁₋₈alkyl, C₃₋₈cycloalkyl, arylC₁₋₅alkyl or heteroarylC₁₋₅alkyl, the latter three groups being optionally substituted by one or more halogen, amino, hydroxy, C₁₋₆alkyl, C₁₋₆alkoxy, SR¹² or NR¹⁰R¹¹; R⁵ is independently hydrogen, C₁₋₆alkyl or C₃₋₆cycloalkyl; R⁶ is independently hydrogen, C₁₋₆alkyl or C₃₋₆cycloalkyl; R⁷ is independently hydrogen, C₁₋₆alkyl or C₃₋₆cycloalkyl; R⁸ is independently hydrogen, aryl, heteroaryl or C₁₋₆alkyl optionally substituted with one or more aryl, heteroaryl, halogen, amino, hydroxy, carboxy, CONR¹²R¹³, SO₂NR¹²R¹³, SO₂R¹², NHSO₂R¹², NHCOR¹², C₁₋₆alkyl, C₃₋₆cycloalkyl, C₁₋₆alkoxy, SR¹² or NR¹⁰R¹¹; or a pharmaceutically acceptable salt thereof.

Aryl groups include phenyl and naphthyl. Heteroaryl groups include 5- or 6-membered, 5,6- or 6,6-fused heterocyclic rings containing one or more heteroatoms selected from N, S or O. Examples include pyridinyl, pyrimidinyl, thiazolyl, oxazolyl, pyrazole, imidazolyl, furyl, thienyl, quinolinyl, isoquinolinyl, benzimidazolyl, benzofuryl, benzothienyl and indolyl.

Aryl and heteroaryl groups can be optionally substituted by on or more of the following groups; halogen, amino, hydroxy, cyano, nitro, carboxy, CONR¹²R¹³, SO₂NR¹²R¹³, SO₂R¹², trifluoromethyl, NHSO₂R¹², NHCOR¹², ethylenedioxy, methylenedioxy, C₁₋₆alkyl, C₁₋₆alkoxy, C₁₋₆alkyl NR¹⁰R¹¹, SR¹² or NR¹⁰R¹¹.

Certain compounds of formula (I) are capable of existing in stereoisomeric forms. It will be understood that the invention encompasses all geometric and optical isomers of the compounds of formula (I) and mixtures thereof including racemates. Tautomers and mixtures thereof also form an aspect of the present invention.

Preferably R¹ is hydrogen or C₁₋₆alkyl, more preferably methyl and R² is CH₂R⁹ or CH₂CH₂R⁹ where R⁹ is phenyl or a 5- or 6-membered aromatic ring containing one or two heteroatoms and optionally substituted by C₁₋₆alkyl. More preferably R² is CH₂R⁹ or CH₂CH₂R⁹ where R⁹ is phenyl, pyridyl or oxazole substituted by methyl.

Alternatively R¹ and R² form a piperidine, piperazine, pyrrolidine, morpholine, or thiomorpholine ring optionally substituted by CH₂OH, CH₂CH₂OH, hydroxy, CONH₂, phenyl, phenoxy, C(O)-furyl, the latter three groups being optionally substituted by halogen, in particular chloro.

Preferably Het is pyrimidine ring.

Preferably R³ is hydrogen.

Preferably R⁴ is hydrogen.

Preferably R⁵ is C₁₋₆alkyl, more preferably iso-butyl.

Preferably R⁶ is hydrogen.

Preferably R⁷ and R⁸ are both hydrogen.

Preferred compounds of the invention include:

-   N˜1˜-[Cyano(2-methoxyphenyl)methyl]-N˜2˜-(2-morpholin-4-ylpyrimidin-4-yl)-L-leucinamide -   N˜1˜-[Cyano(2-methoxyphenyl)methyl]-N˜2˜-(2-piperazin-1-ylpyrimidin-4-yl)-L-leucinamide, -   N-[Cyano(2-methoxyphenyl)methyl]-N-(2-morpholin-4-ylpyrimidin-4-yl)-L-phenylalaninamide -   N˜1˜-[Cyano(2-methoxyphenyl)methyl]-3-cyclohexyl-N˜2˜-(2-morpholin-4-ylpyrimidin-4-yl)-L-alaninamide -   N-[2-(Benzylamino)pyrimidin-4-yl]-N-(cyanomethyl)-L-phenylalaninamide -   N-{2-[Benzyl(methyl)amino]pyrimidin-4-yl}-N-(cyanomethyl)-L-phenylalaninamide -   N-{2-[4-(4-Chlorophenyl)piperazin-1-yl]pyrimidin-4-yl}-N-(cyanomethyl)-L-phenylalaninamide -   N˜2˜-[2-(Benzylamino)pyrimidin-4-yl]-N˜1˜-(cyanomethyl)-3-cyclohexyl-L-alaninamide -   N˜2˜-{2-[Benzyl(methyl)amino]pyrimidin-4-yl}-N˜1˜-(cyanomethyl)-3-cyclohexyl-L-alaninamide -   N˜2˜-{2-[4-(4-Chlorophenyl)piperazin-1-yl]pyrimidin-4-yl}-N˜1˜-(cyanomethyl)-3-cyclohexyl-L-alaninamide -   N˜1˜-(Cyanomethyl)-N˜2˜-(4-morpholin-4-ylpyrimidin-2-yl)-L-leucinamide -   N˜1˜-(Cyanomethyl)-N˜2˜-(2-morpholin-4-ylpyrimidin-4-yl)-L-leucinamide -   N˜1˜-(Cyanomethyl)-N˜2˜-[2-(4-hydroxy-4-phenylpiperidin-1-yl)pyrimidin-4-yl]-L-leucinamide -   N˜1˜-(Cyanomethyl)-N˜2˜-{2-[methyl(pyridin-3-ylmethyl)amino]pyrimidin-4-yl}-L-leucinamide -   N˜2˜-{2-[Benzyl(methyl)amino]pyrimidin-4-yl}-N˜1˜-(cyanomethyl)-L-leucinamide -   N˜2˜-{2-[4-(4-Chlorophenyl)piperazin-1-yl]pyrimidin-4-yl}-N˜1˜-(cyanomethyl)-L-leucinamide, -   N˜2˜-{2-[4-(5-Chloropyridin-2-yl)piperazin-1-yl]pyrimidin-4-yl}-N˜1˜-(cyanomethyl)-L-leucinamide, -   N˜1˜-(Cyanomethyl)-N˜2˜-{2-[methyl(thien-3-ylmethyl)amino]pyrimidin-4-yl}-L-leucinamide -   N˜1˜-(Cyanomethyl)-N˜2˜-(2-thiomorpholin-4-ylpyrimidin-4-yl)-L-leucinamide -   N˜1˜-(Cyanomethyl)-N˜2˜-[2-(4-phenylpiperazin-1-yl)pyrimidin-4-yl]-L-leucinamide -   N˜1˜-(Cyanomethyl)-N˜2˜-{2-[2-(hydroxymethyl)piperidin-1-yl]pyrimidin-4-yl}-L-leucinamide -   N˜1˜-(Cyanomethyl)-N˜2˜-{2-[(2R)-2-(hydroxymethyl)pyrrolidin-1-yl]pyrimidin-4-yl}-L-leucinamide -   N˜1˜-(Cyanomethyl)-N˜2˜-[2-(4-hydroxypiperidin-1-yl)pyrimidin-4-yl]-L-leucinamide -   N˜1˜-(Cyanomethyl)-N˜2˜-{2-[4-(2-furoyl)piperazin-1-yl]pyrimidin-4-yl}-L-leucinamide, -   N˜1˜-(Cyanomethyl)-N˜2˜-{2-[methyl(2-pyridin-2-ylethyl)amino]pyrimidin-4-yl}-L-leucinamide -   N˜2˜-[2-(4-Benzylpiperidin-1-yl)pyrimidin-4-yl]-N˜1˜-(cyanomethyl)-L-leucinamide -   N˜1˜-(Cyanomethyl)-N˜2˜-[2-(4-pyridin-2-ylpiperazin-1-yl)pyrimidin-4-yl]-L-leucinamide -   N˜1˜-(Cyanomethyl)-N˜2˜-[2-(4-phenylpiperidin-1-yl)pyrimidin-4-yl]-L-leucinamide -   N˜1˜-(Cyanomethyl)-N˜2˜-{2-[4-(2-hydroxyethyl)piperidin-1-yl]pyrimidin-4-yl}-L-leucinamide -   N˜2˜-{2-[4-(3-Chlorophenyl)piperazin-1-yl]pyrimidin-4-yl}-N˜1˜-(cyanomethyl)-L-leucinamide -   N˜1˜-(Cyanomethyl)-N˜2˜-[2-(4-phenoxypiperidin-1-yl)pyrimidin-4-yl]-L-leucinamide -   N˜1˜-(Cyanomethyl)-N˜2˜-[2-(3-phenylpyrrolidin-1-yl)pyrimidin-4-yl]-L-leucinamide -   N˜1˜-(Cyanomethyl)-N˜2˜-(2-{methyl[(3-methylisoxazol-5-yl)methyl]amino}pyrimidin-4-yl)-L-leucinamide     and pharmaceutically acceptable salts thereof.

The present invention further provides a process for the preparation of a compound of formula (I) which comprises

-   -   (i) reaction of a compound of general formula (II)

wherein L represents a leaving group (e.g. halide, sulphide, sulfoxide or sulphone group), preferably the sulphide is oxidised to a sulphoxide or sulphone group before displacement. An oxidising agent such as a peracid may be used, for example meta-chloroperbenzoic acid in dichloromethane at room temperature.

L may be displaced by NR¹R² respectively where R¹ and R² are defined in formula (I). The reaction may be performed in an inert solvent for example dioxane, N,N-dimethylformamide at ambient temperature or with heating, usually with a base present for example N,N-diisopropylethylamine.

X may be CN, or a group that can be readily converted into a nitrile, for example C1-6alkoxycarbonyl, CONH₂ or CO₂H.

Compounds of formula (II) may be prepared from compounds of formula (III) by displacement of a leaving group L¹ from compounds of formula (IV).

Wherein L¹ represents a leaving group (e.g. halide, sulphide, sulfoxide or sulphone group), preferably the sulphide is oxidised to a sulphoxide or sulphone group before displacement. An oxidising agent such as a peracid may be used, for example meta-chloroperbenzoic acid in dichloromethane at room temperature. The reaction may be performed in an inert solvent for example dioxane, N,N-dimethylformamide at ambient temperature or with heating, usually with a base present for example N,N-diisopropylethylamine.

Compounds of formula (III) may be prepared from the reaction of compounds of formula (V) with compounds of formula (VI) using an appropriate coupling agent, for example N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide, carbonyl diimidazole. Alternatively the acid may be activated by formation of the acid chloride using for example, oxalyl chloride.

P is a nitrogen protecting group for example tert-butylcarbamate, benzyl carbamate, benzyl.

Compound of general formula (II) may also be prepared from the reaction of compounds of formula (VII) with compounds of formula (VI) using an appropriate coupling agent, for example N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide, carbonyl diimidazole. Alternatively the acid may be activated by formation of the acid chloride using for example, oxalyl chloride.

-   -   (ii) reaction of a compound of general formula (VII) with         compounds of formula (III) or reaction of a compound of general         formula (IX) with a compound of general formula (VI).

According to a further feature of the invention there is provided a compound of the formula (I), or a pharmaceutically acceptable salt thereof, for use as a therapeutic agent.

According to a further feature of the present invention there is provided a method for producing inhibition of a cysteine protease in a warm blooded animal, such as man, in need of such treatment, which comprises administering to said animal an effective amount of a compound of the present invention, or a pharmaceutically acceptable salt thereof. In particular the compounds of the invention are useful in the treatment of inflammation and immune disorders such as, but not limited to, asthma, rheumatoid arthritis, COPD, multiple sclerosis, Crohn's disease, Alzheimers and pain, such as neuropathic pain. Preferably the compounds of the invention are used to treat pain, especially neuropathic pain.

The invention also provides a compound of the formula (I), or a pharmaceutically acceptable salt thereof, for use as a medicament; and the use of a compound of the formula (I) of the present invention, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for use in the inhibition of a cysteine protease in a warm blooded animal, such as man.

In particular the invention provides the use of a compound of the formula (I) of the present invention, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for use in the inhibition of Cathepsin S in a warm blooded animal, such as man. In order to use a compound of the formula (I) or a pharmaceutically acceptable salt thereof for the therapeutic treatment of mammals including humans, in particular in the inhibition of a cysteine protease, it is normally formulated in accordance with standard pharmaceutical practice as a pharmaceutical composition.

Therefore in another aspect the present invention provides a pharmaceutical composition which comprises a compound of the formula (I) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable diluent or carrier.

The pharmaceutical compositions of this invention may be administered in standard manner for the disease condition that it is desired to treat, for example by oral, rectal or parenteral administration. For these purposes the compounds of this invention may be formulated by means known in the art into the form of, for example, tablets, capsules, aqueous or oily solutions or suspensions, (lipid) emulsions, dispersible powders, suppositories, ointments, creams, drops and sterile injectable aqueous or oily solutions or suspensions.

A suitable pharmaceutical composition of this invention is one suitable for oral administration in unit dosage form, for example a tablet or capsule which contains between 100 mg and 1 g of the compound of this invention.

In another aspect a pharmaceutical composition of the invention is one suitable for intravenous, subcutaneous or intramuscular injection.

Each patient may receive, for example, an intravenous, subcutaneous or intramuscular dose of 1 mgkg⁻¹ to 100 mgkg⁻¹ of the compound, preferably in the range of 5 mgkg⁻¹ to 20 mgkg⁻¹ of this invention, the composition being administered 1 to 4 times per day. The intravenous, subcutaneous and intramuscular dose may be given by means of a bolus injection. Alternatively the intravenous dose may be given by continuous infusion over a period of time. Alternatively each patient will receive a daily oral dose which is approximately equivalent to the daily parenteral dose, the composition being administered 1 to 4 times per day.

The following illustrate representative pharmaceutical dosage forms containing the compound of formula (I), or a pharmaceutically-acceptable salt thereof (hereafter compound X), for therapeutic or prophylactic use in humans:

(a) Tablet I mg/tablet Compound X. 100 Lactose Ph.Eur. 179 Croscarmellose sodium 12.0 Polyvinylpyrrolidone 6 Magnesium stearate 3.0 (b) Tablet II mg/tablet Compound X 50 Lactose Ph.Eur. 229 Croscarmellose sodium 12.0 Polyvinylpyrrolidone 6 Magnesium stearate 3.0 (c) Tablet III mg/tablet Compound X 1.0 Lactose Ph.Eur. 92 Croscarmellose sodium 4.0 Polyvinylpyrrolidone 2.0 Magnesium stearate 1.0 (d) Capsule mg/capsule Compound X 10 Lactose Ph.Eur. 389 Croscarmellose sodium 100 Magnesium stearate 1. (e) Injection I (50 mg/ml) Compound X 5.0% w/v Isotonic aqueous solution to 100%

Buffers, pharmaceutically-acceptable cosolvents such as polyethylene glycol, polypropylene glycol, glycerol or ethanol or complexing agents such as hydroxy-propyl β cyclodextrin may be used to aid formulation.

Note

The above formulations may be obtained by conventional procedures well known in the pharmaceutical art. The tablets (a)-(c) may be enteric coated by conventional means, for example to provide a coating of cellulose acetate phthalate.

The following examples illustrate the invention.

EXAMPLE 1 N˜1˜-[Cyano(2-methoxyphenyl)methyl]-N˜2˜-(2-morpholin-4-ylpyrimidin-4-yl)-L-leucinamide (i) N˜2˜-(tert-Butoxycarbonyl)-N˜1˜-[cyano(2-methoxyphenyl)methyl]-L-leucinamide

1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (2.9 g) and 1-hydroxybenzotriazole hydrate (2.0 g) were added to a solution of 2-methoxyphenylamino acetonitrile (2.0 g) and N-tert-butoxycarbonyl L-leucine (2.5 g) in N,N-dimethylformamide (20 ml) at room temperature followed by N,N-diisopropylethylamine (5.3 ml) and stirred at room temperature overnight. The mixture was diluted with water, extracted into ethyl acetate and dried (MgSO₄). The solvent was removed under vacuum to leave an oil which was subjected to column chromatography on silica eluting with isohexane/ethyl acetate 2:1 to give a colourless oil (3.7 g).

MS: APCI(+ve) 249 (M-Boc-CN+1)

(ii) N˜1˜-[Cyano(2-methoxyphenyl)methyl]-L-leucinamide

The product from step (i) (3.70 g) in formic acid (40 ml) was stirred for 90 min at room temperature then the solvent was removed under vacuum to give a yellow oil (2.7 g).

MS: APCI(+ve) 276 (M-Boc+1)

(iii) N˜1˜-[Cyano(2-methoxyphenyl)methyl]-N˜2˜-(2-fluoropyrimidin-4-yl)-L-leucinamide

A solution of the product from step (ii) (2.7 g) and N,N-diisopropylethylamine (1.7 ml) in tetrahydrofuran (40 ml) was added dropwise to a solution of 2,4-difluoropyrimidine (1.15 g) in tetrahydrofuran (40 ml) and N,N-diisopropylethylamine (1.7 ml). After stirring at room temperature overnight the solvent was removed under vacuum to yield a crude oil which was subjected to column chromatography on silica eluting with dichloromethane/ethyl acetate 2:1 to give a colourless oil (1.50 g).

MS: APCI(+ve) 372 (M+1)

(iv) N˜1˜-[Cyano(2-methoxyphenyl)methyl]-N˜2˜-(2-morpholin-4-ylpyrimidin-4-yl)-L-leucinamide

The product from step (iii) (0.5 g), morpholine (0.12 ml) and N,N-diisopropylethylamine (0.24 ml) in tetrahydrofuran (20 ml) was stirred at room temperature overnight. The solvent was removed under vacuum to yield a crude oil which was subjected to column chromatography on silica eluting with ethyl acetate/isohexane 3:1 to give a white solid (0.4 g).

MS: APCI(+ve) 439 (M+1)

1H NMR: δ (DMSO) 9.40 (1H, m), 9.08 (1H, m), 7.78-7.12 (5H, m), 6.10-6.08 (1H, d), 5.80 (1H, m), 4.60-4.40 (1H, m), 3.84-3.51 (11H, m), 1.80-1.20 (3H, m), 0.96-0.84 (6H, m).

EXAMPLE 2 N˜1˜-[Cyano(2-methoxyphenyl)methyl]-N˜2˜-(2-piperazin-1-ylpyrimidin-4-yl)-L-leucinamide, Trifluoroacetate Salt

The title compound was prepared according to the procedure in example 1 step (iv) using piperazine.

MS: APCI(+ve) 438 (M+1)

1H NMR: δ (DMSO) 8.83-8.81 (2H, m), 7.79-6.97 (5H, m), 6.09-6.02 (2H, m), 4.40 (1H, m), 3.85 (7H, bm), 3.13-3.05 (4H, m), 1.68-1.49 (3H, m), 0.94-0.84 (6H, m).

EXAMPLE 3 N-[Cyano(2-methoxyphenyl)methyl]-N-(2-morpholin-4-ylpyrimidin-4-yl)-L-phenylalaninamide (i) N-(tert-Butoxycarbonyl)-N-[cyano(2-methoxyphenyl)methyl]-L-phenylalaninamide

The sub-title compound was prepared from N-butoxycarbonyl-L-phenylalanine (1.32 g) by the method of example 1 step (i). Yield 2.05 g.

MS: APCI(+ve) 310 (M-Boc+1)

(ii) N-[Cyano(2-methoxyphenyl)methyl]-N-(2-fluoropyrimidin-4-yl)-L-phenylalaninamide

The sub-title compound was prepared from the product of step (i) (2.05 g) by the method of example 1 steps (ii) and (iii). Yield 0.57 g.

MS: APCI(+ve) 406 (M+1)

(iii) N-[Cyano(2-methoxyphenyl)methyl]-N-(2-morpholin-4-ylpyrimidin-4-yl)-L-phenylalaninamide

The title compound was prepared from the product of step (ii) (0.25 g) by the method of example 1 step (iv). Yield 0.078 g.

MS: APCI(+ve) 473 (M+1)

NMR: δ (DMSO) 9.29 and 9.15 (1H, 2×d), 7.73 and 7.69 (1H, 2×d), 7.45-7.40 (2H, m), 7.33-7.17 (6H, m), 7.11 (1H, m), 7.00 (1H, m), 6.08 (1H, dd), 5.88 and 5.85 (1H, 2×d), 4.64 (1H, brs), 3.83 and 3.80 (3H, 2×s), 3.58 (4H, m), 3.47 (4H, m), 3.05-2.82 (2H, m).

EXAMPLE 4 N˜1˜-[Cyano(2-methoxyphenyl)methyl]-3-cyclohexyl-N˜2˜-(2-morpholin-4-ylpyrimidin-4-yl)-L-alaninamide (i) N-(tert-Butoxycarbonyl)-N-[cyano(2-methoxyphenyl)methyl]-3-cyclohexyl-L-alaninamide

The sub-title compound was prepared from N-butoxycarbonyl-beta-cyclohexyl-L-alanine (1.36 g) by the method of example 1 step (i). Yield 1.99 g. Used directly in the next step.

(ii) N˜1˜-[Cyano(2-methoxyphenyl)methyl]-3-cyclohexyl-N˜2˜-(2-fluoropyrimidin-4-yl)-L-alaninamide

The sub-title compound was prepared from the product of step (i) (1.99 g) by the method of example 1 steps (ii) and (iii). Yield 0.12 g.

MS: APCI(+ve) 412 (M+1)

(iii) N˜1˜-[Cyano(2-methoxyphenyl)methyl]-3-cyclohexyl-N˜2˜-(2-morpholin-4-ylpyrimidin-4-yl)-L-alaninamide

The title compound was prepared from the product of step (ii) (0.12 g) by the method of example 1 step (iv). Yield 0.087 g.

MS: APCI(+ve) 479 (M+1)

NMR: δ (DMSO) 9.18 and 9.06 (1H, 2×d), 7.76 and 7.72 (1H, 2×d), 7.49-7.37 (2H, m), 7.24 (1H, brs), 7.11 (1H, d), 7.02 (1H, t), 6.09 (1H, m), 5.91 and 5.88 (1H, 2×d), 4.46 and 4.36 (1H, 2×brs), 3.82 and 3.80 (3H, 2×s), 3.60 (4H, m), 3.47 (4H, m), 1.76-1.36 (8H, m), 1.24-1.09 (3H, m), 0.98-0.83 (2H, m).

EXAMPLE 5 N-[2-(Benzylamino)pyrimidin-4-yl]-N-(cyanomethyl)-L-phenylalaninamide (i) N-(tert-Butoxycarbonyl)-N-(cyanomethyl)-L-phenylalaninamide

The sub-title compound was prepared from aminoacetonitrile hydrochloride by the method of example 1 step (i).

MS: APCI(+ve) 204 (M-Boc+1)

(ii) N-(Cyanomethyl)-N-(2-fluoropyrimidin-4-yl)-L-phenylalaninamide

The sub-title compound was prepared from the product of step (i) (3.5 g) by the method of example 1 steps (ii) and (iii). Yield 1.11 g.

MS: APCI(+ve) 300 (M+1)

(iii) N-[2-(Benzylamino)pyrimidin-4-yl]-N-(cyanomethyl)-L-phenylalaninamide

The title compound was prepared from the product from step (ii) (0.2 g) and benzylamine (0.37 ml) by the method of example 1 step (iv). Yield 0.11 g.

MS: APCI(+ve) 387 (M+1)

NMR: δ (DMSO) 8.60 (1H, brs), 7.61 (1H, d), 7.29-7.14 (10H, m), 6.93 (1H, brs), 5.78 (1H, d), 4.64 (1H, brs), 4.47-4.33 (2H, m), 4.05 (2H, brs), 3.03 (1H, dd), 2.85 (1H, m).

EXAMPLE 6 N-{2-[Benzyl(methyl)amino]pyrimidin-4-yl}-N-(cyanomethyl)-L-phenylalaninamide

The title compound was prepared from the product of example 5 step (ii) (0.2 g) and N-benzylmethylamine by the method of example 1 step (iv). Yield 0.18 g.

MS: APCI(+ve) 401 (M+1)

NMR: δ (DMSO) 8.69 (1H, brs), 7.71 (1H, d), 7.33-7.15 (10H, m), 5.84 (1H, d), 4.75 (2H, q), 4.62 (1H, brs), 4.03 (2H, brs), 2.99 (1H, dd), 2.94 (3H, s), 2.86 (1H, m).

EXAMPLE 7 N-{2-[4-(4-Chlorophenyl)piperazin-1-yl]pyrimidin-4-yl}-N-(cyanomethyl)-L-phenylalaninamide

The title compound was prepared from the product of example 5 step (ii) (0.2 g) and 4(4-chlorophenyl)piperazine by the method of example 1 step (iv). Yield 0.18 g.

MS: APCI(+ve) 476 (M+1)

NMR: δ (DMSO) 8.77 (1H, t), 7.72 (1H, d), 7.40 (1H, brs), 7.31-7.17 (7H, m), 6.98 (2H, d), 5.86 (1H, d), 4.54 (1H, brs), 4.13 (2H, m), 3.74 (4H, m), 3.12 (4H, m), 3.01 (1H, dd), 2.89 (1H, m).

EXAMPLE 8 N˜2˜-[2-(Benzylamino)pyrimidin-4-yl]-N˜1˜-(cyanomethyl)-3-cyclohexyl-L-alaninamide (i) N-(tert-butoxycarbonyl)-N-(cyanomethyl)-3-cyclohexyl-L-alaninamide

The sub-title compound was prepared from N-butoxycarbonyl-beta-cyclohexyl-L-alanine (5.0 g) and aminoacetonitrile hydrochloride (1.71 g) by the method of example 1 step (i). Yield 4.09 g.

MS: APCI(+ve) 210 (M-Boc+H)

(ii) N˜1˜-(Cyanomethyl)-3-cyclohexyl-N˜2˜-(2-fluoropyrimidin-4-yl)-L-alaninamide

The sub-title compound was prepared from the product of step (i) (4.09 g) by the method of example 1 steps (ii) and (iii). Yield 1.00 g.

MS: APCI(+ve) 306 (M+1)

(iii) N˜2˜-[2-(Benzylamino)pyrimidin-4-yl]-N˜1˜-(cyanomethyl)-3-cyclohexyl-L-alaninamide

The title compound was prepared from the product of step (ii) (0.2 g) by the method of example 1 step (iv). Yield 0.05 g.

MS: APCI(+ve) 393 (M+1)

NMR: δ (DMSO) 8.48 (1H, brs), 7.64 (1H, d), 7.31-7.24 (4H, m), 7.17 (1H, m), 7.09 (1H, brs), 6.93 (1H, brs), 5.81 (1H, d), 4.47-4.36 (3H, m), 4.04 (2H, d), 1.75-1.47 (7H, m), 1.31 (1H, m), 1.19-1.09 (3H, m), 0.86 (2H, m).

EXAMPLE 9 N˜2˜-{2-[Benzyl(methyl)amino]pyrimidin-4-yl}-N˜1˜-(cyanomethyl)-3-cyclohexyl-L-alaninamide

The title compound was prepared from the product of example 8 step (ii) (0.2 g) and N-benzylmethylamine (0.43 ml) by the method of example 1 step (iv). Yield 0.13 g.

MS: APCI(+ve) 407 (M+1)

NMR: δ (DMSO) 8.57 (1H, brs), 7.73 (1H, d), 7.31-7.27 (2H, m), 7.23-7.19 (4H, m), 5.85 (1H, d), 4.80 (2H, m), 4.42 (1H, brs), 4.02 (2H, m), 2.95 (3H, s), 1.69-1.44 (7H, m), 1.35 (1H, m), 1.24-1.07 (3H, m), 0.92-0.81 (2H, m).

EXAMPLE 10 N˜2˜-{2-[4-(4-Chlorophenyl)piperazin-1-yl]pyrimidin-4-yl}-N˜1˜-(cyanomethyl)-3-cyclohexyl-L-alaninamide

The title compound was prepared from the product of example 8 step (ii) (0.2 g) and 4(4-chlorophenyl)piperazine (0.66 g) by the method of example 1 step (iv). Yield 0.2 g.

MS: APCI(+ve) 482 (M+1)

NMR: δ (DMSO) 8.66 (1H, t), 7.75 (1H, d), 7.25 (3H, d), 6.98 (2H, d), 5.89 (1H, d), 4.35 (1H, brs), 4.12 (2H, d), 3.75 (4H, m), 3.13 (4H, m), 1.73-1.46 (7H, m), 1.37 (1H, m), 1.24-1.07 (3H, m), 0.97-0.87 (2H, m).

EXAMPLE 11 N˜1˜-(Cyanomethyl)-N˜2˜-(4-morpholin-4-ylpyrimidin-2-yl)-L-leucinamide (i) N˜2˜-(tert-Butoxycarbonyl)-N˜1˜-(cyanomethyl)-L-leucinamide

The sub-title compound was prepared according to the procedure of example 1 step (i) with amino acetonitrile hydrochloride (2.22 g) and N-tert-butoxy S-leucine (5 g).

MS: APCI(+ve) 270 (M+1)

(ii) N˜1˜-(Cyanomethyl)-N˜2˜-(4-fluoropyrimidin-2-yl)-L-leucinamide and N˜1˜-(Cyanomethyl)-N˜2˜-(2-fluoropyrimidin-4-yl)-L-leucinamide

The sub-title compounds were prepared from the product of step (i) (4.3 g) according to the procedure of example 1 steps (ii) and (iii).

N˜1˜-(Cyanomethyl)-N˜2˜-(4-fluoropyrimidin-2-yl)-L-leucinamide

Yield 0.38 g

MS: APCI(+ve) 266 (M+1)

N˜1˜-(Cyanomethyl)-N˜2˜-(2-fluoropyrimidin-4-yl)-L-leucinamide

Yield 3.8 g

MS: APCI(+ve) 266 (M+1)

(iii) N˜1˜-(Cyanomethyl)-N-2˜-(4-morpholin-4-ylpyrimidin-2-yl)-L-leucinamide

The title compound was prepared according to the procedure of example 1 step (iv) using N˜1˜-(cyanomethyl)-N˜2˜-(4-fluoropyrimidin-2-yl)-L-leucinamide. Yield 0.2 g

MS: APCI(+ve) 333 (M+1)

1H NMR: δ (DMSO) 8.49-8.46 (1H, t), 7.83-7.81 (1H, d), 6.63 (1H, bm), 6.06-6.04 (1H, d), 4.25-4.05 (3H, m), 3.63-3.47 (8H, m), 1.75-1.39 (3H, m), 0.90-0.84 (6H, m).

EXAMPLE 12 N˜1˜-(Cyanomethyl)-N˜2˜-(2-morpholin-4-ylpyrimidin-4-yl)-L-leucinamide

The title compound was prepared from N˜1˜-(cyanomethyl)-N˜2˜-(2-fluoropyrimidin-4-yl)-L-leucinamide (example 11 step (iii)) according to the procedure of example 1 step (iv). Yield 0.17 g

MS: APCI(+ve) 333 (M+1)

1H NMR: δ (DMSO) 8.64-8.60 (1H, t), 7.74-7.72 (1H, d), 7.24-7.23 (1H, d), 5.89-5.82 (1H, d), 4.31-4.08 (3H, m), 3.58 (8H, m), 1.72-1.39 (3H, m), 0.92-0.84 (6H, m).

Examples 13-34 were prepared according to the procedures of example 1 step (iv) using N˜1˜-(cyanomethyl)-N˜2˜-(2-fluoropyrimidin-4-yl)-L-leucinamide (example 11 step (iii)) and the appropriate amine.

EXAMPLE 13 N˜1˜-(Cyanomethyl)-N˜2˜-[2-(4-hydroxy-4-phenylpiperidin-1-yl)pyrinidin-4-yl]-L-leucinamide

MS: APCI(+ve) 423 (M+1)

1H NMR: δ (DMSO) 8.65-8.61 (1H, t), 7.73-7.14 (7H, m), 5.84-5.82 (1H, d), 5.00-4.39 (4H, m), 4.08-4.03 (2H, m), 3.20-3.12 (2H, m), 1.90-1.35 (7H, m), 0.92-0.85 (6H, m).

EXAMPLE 14 N˜1˜-(Cyanomethyl)-N˜2˜-{2-[methyl(pyridin-3-ylmethyl)amino]pyrimidin-4-yl}-L-leucinamide

MS: APCI(+ve) 368 (M+1)

1H NMR: δ (DMSO) 8.59-7.20 (7H, m), 5.89-5.87 (1H, d), 4.68 & 4.37 (3H, m), 4.08-4.02 (2H, m), 2.99 (3H, s), 1.68-1.35 (3H, m), 0.93-0.80 (6H, m).

EXAMPLE 15 N˜2˜-{2-[enzyl(methyl)amino]pyrimidin-4-yl}-N˜1˜-(cyanomethyl)-L-leucinamide

MS: APCI(+ve) 367 (M+1)

1H NMR: δ (DMSO) 8.57-8.54 (1H, t), 7.74 (1H, d), 7.31-7.18 (6H, m), 5.87-5.85 (1H, d), 4.82-4.00 (5H, m), 2.95 (3H, s), 1.71-1.40 (3H, m), 0.89-0.81 (6H, m).

EXAMPLE 16 N˜2˜-{2-[4-(4-Chlorophenyl)piperazin-1-yl]pyrimidin-4-yl}-N˜1˜-(cyanomethyl)-L-leucinamide, Trifluoroacetate Salt

MS: APCI(+ve) 442 (M+1)

1H NMR: δ (DMSO) 9.02-9.01 (2H, m), 7.75-6.98 (5H, m), 6.24-6.22 (1H, d), 4.48-4.13 (3H, m), 3.82-3.55 (8H, m), 1.66-1.50 (3H, m), 0.95-0.88 (6H, m).

EXAMPLE 17 N˜2˜-{2-[4-(5-Chloropyridin-2-yl)piperazin-1-yl]pyrimidin-4-yl}-N˜1˜-(cyanomethyl)-L-leucinamide, Bis Trifluoroacetate Salt

MS: APCI(+ve) 443 (M+1)

1H NMR: δ (DMSO) 9.03-9.01 (2H, m), 8.15-6.90 (4H, m), 6.25-6.23 (1H, d), 4.49 (1H, m), 4.23-4.18 (2H, d), 3.80-3.66 (8H, m), 1.66-1.51 (3H, m), 0.95-0.88 (6H, m).

EXAMPLE 18 N˜1˜-(Cyanomethyl)-N˜2˜-{2-[methyl(thien-3-ylmethyl)amino]pyrimidin-4-yl}-L-leucinamide

MS: APCI(+ve) 373 (M+1)

EXAMPLE 19 N˜1˜-(Cyanomethyl)-N˜2˜-(2-thiomorpholin-4-ylpyrimidin-4-yl)-L-leucinamide

MS: APCI(+ve) 349 (M+1)

EXAMPLE 20 N˜1˜-(Cyanomethyl)-N˜2˜-[2-(4-phenylpiperazin-1-yl)pyrimidin-4-yl]-L-leucinamide

MS: APCI(+ve) 408 (M+1)

EXAMPLE 21 N˜1˜-(Cyanomethyl)-N˜2˜-{2-[2-(hydroxymethyl)piperidin-1-yl]pyrimidin-4-yl}-L-leucinamide

MS: APCI(+ve) 361 (M+1)

EXAMPLE 22 N˜1˜-(Cyanomethyl)-N˜2˜-{2-[(2R)-2-(hydroxymethyl)pyrrolidin-1-yl]pyrimidin-4-yl}-L-leucinamide

MS: APCI(+ve) 347 (M+1)

EXAMPLE 23 N˜1˜-(Cyanomethyl)-N˜2˜-[2-(4-hydroxypiperidin-1-yl)pyrimidin-4-yl]-L-leucinamide

MS: APCI(+ve) 347 (M+1)

EXAMPLE 24 N˜1˜-(Cyanomethyl)-N˜2˜-{2-[4-(2-furoyl)piperazin-1-yl]pyrimidin-4-yl}-L-leucinamide

MS: APCI(+ve) 426 (M+1)

EXAMPLE 25 N˜2˜-{2-[3-(Aminocarbonyl)piperidin-1-yl]pyrimidin-4-yl}-N˜1˜-(cyanomethyl)-L-leucinamide

MS: APCI(+ve) 374 (M+1)

EXAMPLE 26 N˜1˜-(Cyanomethyl)-N˜2˜-{2-[methyl(2-pyridin-2-ylethyl)amino]pyridin-4-yl}-L-leucinamide

MS: APCI(+ve) 382 (M+1)

EXAMPLE 27 N˜2˜-[2-(4-Benzylpiperidin-1-yl)pyrimidin-4-yl]-N˜1˜-(cyanomethyl)-L-leucinamide

MS: APCI(+ve) 421 (M+1)

EXAMPLE 28 N˜1˜-(Cyanomethyl)-N˜2˜-[2-(4-pyridin-2-ylpiperazin-1-yl)pyrimidin-4-yl]-L-leucinamide

MS: APCI(+ve) 409 (M+1)

EXAMPLE 29 N˜1˜-(Cyanomethyl)-N˜2˜-[2-(4-phenylpiperidin-1-yl)pyrimidin-4-yl]-L-leucinamide

MS: APCI(+ve) 407 (M+1)

EXAMPLE 30 N˜1˜-(Cyanomethyl)-N˜2˜-{2-[4-(2-hydroxyethyl)piperidin-1-yl]pyrimidin-4-yl}-L-leucinamide

MS: APCI(+ve) 375 (M+1)

EXAMPLE 31 N˜2˜-{2-[4-(3-Chlorophenyl)piperazin-1-yl]pyrimidin-4-yl}-N˜1˜-(cyanomethyl)-L-leucinamide

MS: APCI(+ve) 442/4 (M+1)

EXAMPLE 32 N˜1˜-(Cyanomethyl)-N˜2˜-[2-(4-phenoxypiperidin-1-yl)pyrimidin-4-yl]-L-leucinamide

MS: APCI(+ve) 423 (M+1)

EXAMPLE 33 N˜1˜-(Cyanomethyl)-N˜2˜-[2-(3-phenylpyrrolidin-1-yl)pyrimidin-4-yl]-L-leucinamide

MS: APCI(+ve) 393 (M+1)

EXAMPLE 34 N˜1˜-(Cyanomethyl)-N˜2˜-(2-{methyl[(3-methylisoxazol-5-yl)methyl]amino}pyrimidin-4-yl)-L-leucinamide

MS: APCI(+ve) 372 (M+1)

Measurement of Cathepsin S Activity.

QFRET Technology (Quenched Fluorescent Resonance Energy Transfer) was used to measure the inhibition by test compounds of Cathepsin S-mediated cleavage of the synthetic peptide Z-Val-Val-Arg-AMC. Compounds were screened at five concentrations in duplicate and the pIC₅₀ values reported.

Synthetic substrate, 20□M [final] Z-Val-Val-Arg-AMC in phosphate buffer were added to a 96 well black Optiplate. The assay plates were pre-read for compound auto fluorescence on SpectraMax Gemini at 355 nM excitation and 460 nM emission. 250 pM [final] rHuman Cathepsin S in phosphate buffer was added and incubated for 2 h at room temperature on the SpectraMax Gemini, taking readings every 20 min at 355 nM excitation and 460 nM emission.

Activity Based template (5PTB-8) used the auto fluorescent corrected data to calculate the percentage inhibition for each compound concentration using the relevent plate controls. This data was used to construct inhibition curves and pIC₅₀ estimated by non-linear regression using a 4 parameter logistic model. 

1. A compound of formula (I):

R¹ is independently hydrogen, C₁₋₆alkyl or C₃₋₆cycloalkyl; R² is independently aryl, heteroaryl or a group C₁₋₆alkylR⁹, CO(C₁₋₆alkyl)R⁹ or SO₂(C₁₋₆alkyl)R⁹; Het is a heteroaryl ring chosen from pyridine, pyrimidine, pyrazine, pyridazine or triazine and optionally substituted by halogen, amino, hydroxy, cyano, nitro, carboxy, CONR¹²R¹³, SO₂NR¹²R¹³, SO₂R¹², trifluoromethyl, NHSO₂R¹², NHCOR¹², C₁₋₆alkyl, C₁₋₆alkoxy, SR¹² or NR¹⁰R¹¹; R³ is independently hydrogen, C₁₋₆ alkyl or C₃₋₆cycloalkyl; R⁴ is independently hydrogen, C₁₋₈alkyl, C₃₋₈cycloalkyl, arylC₁₋₅alkyl or heteroarylC₁₋₅alkyl, the latter three groups being optionally substituted by one or more halogen, amino, hydroxy, C₁₋₆alkyl, C_(1-6 l alkoxy, SR) ¹² or NR¹⁰R¹¹; R⁵ is independently hydrogen, C₁₋₆alkyl or C₃₋₆cycloalkyl; R⁶ is independently hydrogen, C₁₋₆alkyl or C₃₋₆cycloalkyl; R⁷ is independently hydrogen, C₁₋₆alkyl or C₃₋₆cycloalkyl; R⁸ is independently hydrogen, aryl, heteroaryl or C₁₋₆alkyl optionally substituted with one or more aryl, heteroaryl, halogen, amino, hydroxy, carboxy, CONR¹²R¹³, SO₂NR¹²R¹³, SO₂R¹², NHSO₂R¹², NHCOR¹², C₁₋₆alkyl, C₃₋₆cycloalkyl, C₁₋₆ alkoxy, SR¹² or NR¹⁰R¹¹; R⁹ is aryl or heteroaryl; R¹⁰ and R¹¹ are independently hydrogen, C₁₋₆alkyl or together with the nitrogen atom to which they are attached form a 5- or 6-membered saturated ring optionally containing a further O, S or NR¹ group; and R¹² and R¹³ are independently hydrogen or C₁₋₆alkyl; or a pharmaceutically acceptable salt thereof.
 2. A compound according to claim 1 in which R¹ is hydrogen or C₁₋₆alkyl and R² is CH₂R⁹ or CH₂CH₂R⁹ where R⁹ is phenyl or a 5- or 6-membered aromatic ring containing one or two heteroatoms and optionally substituted by C₁₋₆alkyl.
 3. A compound according to claim 1 in which R³ is hydrogen.
 4. A compound according to claim 1 in which R⁴ is hydrogen.
 5. A compound according to claim 1 in which R⁵ is hydrogen.
 6. A compound of formula (I) selected from: N-[2-(Benzylamino)pyrimidin-4-yl]-N-(cyanomethyl)-L-phenylalaninamide, N-{2-[Benzyl(methyl)amino]pyrimidin-4-yl}-N-(cyanomethyl)-L-phenylalaninamide, N˜2˜-[2-(Benzylamino)pyrimidin-4-yl]-N˜1˜-(cyanomethyl)-3-cyclohexyl-L-alaninamide, N˜2˜-{2-[Benzyl(methyl)amino]pyrimidin-4-yl}-N˜1˜-(cyanomethyl)-3-cyclohexyl-L-alaninamide, N˜1˜-(Cyanomethyl)-N˜2˜-{2-[methyl(pyridin-3-ylmethyl)amino]pyrimidin-4-yl}-L-leucinamide, N˜2˜-{2-[Benzyl(methyl)amino]pyrimidin-4-yl}-N˜1˜-(cyanomethyl)-L-leucinamide, N˜1˜-(Cyanomethyl)-N˜2˜-{2-[methyl(thien-3-ylmethyl)amino]pyrimidin-4-yl}-L-leucinamide, N˜1˜-(Cyanomethyl)-N˜2˜-{2-[methyl(2-pyridin-2-ylethyl)amino]pyrimidin-4-yl}-L-leucinamide, N˜1˜-(Cyanomethyl)-N˜2˜-(2-{methyl[(3-methylisoxazol-5-yl)methyl]amino}pyrimidin-4-yl)-L-leucinamide, and pharmaceutically acceptable salts thereof.
 7. A pharmaceutical composition which comprises a compound as defined in claim 1 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable diluent or carrier.
 8. A compound according to claim 1 in which R⁴ is phenylC₁₋₅alkyl being optionally substituted by one or more halogen, amino, hydroxy, C₁₋₆alkyl, C₁₋₆alkoxy, SR¹² or NR¹⁰R¹¹.
 9. A compound according to claim 1 in which R⁵ is C₁₋₆alkyl.
 10. A compound according to claim 1 in which R⁵ is iso-butyl.
 11. A compound according to claim 1 in which R⁶ is hydrogen.
 12. A compound according to claim 1 in which R⁷ and R⁸ are both hydrogen.
 13. A compound according to claim 1 in which R⁹ is phenyl, pyridyl or oxazole substituted by methyl.
 14. A pharmaceutical composition which comprises a compound according to claim 13 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable diluent or carrier.
 15. A compound according to claim 1 in which Het is a pyrimidine ring. 